It is known that allergic diseases are largely divided into immunoglobulin (IgE)-mediated diseases and non-IgE-mediated diseases. It is known that when allergens triggering an allergic disease are penetrated into a body, the allergic disease is triggered and worsened by imbalance of Th(helper)1/Th(helper)2 lymphocytes.
In addition, it is known that abnormal differentiation of Th2-cells is induced by action of a cytokine including IL-4 (according to the recent study, when production of IL-4 and IL-5 are reduced, an allergic disease is not improved, and thus IL-4 and IL-5 are also known as unimportant factors in triggering of the allergic disease), cytokines including IL-9, IL-33, and thymic stromal lymphopoietin (TSLP), regulatory T-cell (Treg) families (nTreg, Th3, and iTreg), and newly known effecter cells such as nuocytes, Th9, and Th22, which induce Th2 differentiation.
When microorganisms or chemicals and allergens are penetrated, rather than that TSLP, as a primary inducer of Th2 immune deviation, is produced by epitheliums in the skin, intestines, and lung to stimulate dendritic cells, thereby stimulating production of Th-2 cytokine and directly producing cytokines, a TSLP-primed dendritic cells (DCs) serve to up-regulate costimulatory molecules (molecules of antigen presenting cells) and increase production of Th2-attracting chemokines including thymus and activation-regulated chemokine (CCL17), macrophage-derived chemokine (CCL22), IL-15, and IL-18. Similarly, in the skin, TSLP expression provokes atopic dermatitis.
Meanwhile, large amounts of keratinocytes are expressed in atopic dermatitis patients. That is, an allergen induces amplification of TSLP-mediated Th2 response. When production of IL-25 is increased by an allergen, production of CCL5 (RANTES) and CCL11 (eotaxin-1) is increased, and thus eosinophils remain at a part in which inflammation occurs. In addition, interleukin-33 (IL-33) secreted from necrotized cells generated by reaction to infection and inflammation is expressed in bronchial epithelium, fibroblast, keratinocytes, smooth muscle cells, dendritic cells, mast cells, and macrophages, and serves as a chemoattractant to Th2 cells, in addition to Th2 immune deviation. When IL-33 is administered, Th2 immune deviation, cytokine production, elevated IgE, and mucosal eosinophilic inflammation are induced to cause DC differentiation, thereby inducing expression of major histocompatibility complex class 2, CD86, and IL-6. The activated DC as described above stimulates differentiation of naive CD4+T cells to increase production of IL-5 and IL-13, and IL-33 helps in maturation of a CD34+ mast cell precursor and homing to a tissue. As a result, activation of IL-25, IL-33, and TSLP that are imbalanced in inducing and worsening an allergic disease results in allergic diseases through a pathological and inflammatory process of allergic diseases due to activation of cells inducing and worsening the allergic diseases such as Th cells, mast cells, DCs, eosinophils, and basophils.
As the allergic diseases, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, rash, pollinosis, or asthma is known.
It is reported that atopic dermatitis is expressed 50% at the age of 1, and 80% at the age of 5, and usually is shown as a chronic, relapsing skin disease, for example, eczema on the folds of a body such as antecubital fossa or popliteal fossa. Usually, IgE is increased in a serum, and allergic rhinitis and asthma are accompanied as a person grows. Prevalence in the developed countries varies depending on a reporter in a range from 20 to 30%, and it is reported that in Korea, prevalence is 10% at the age of 6 or less, 6% at the age of 6 to 12, and generally 2% at the age of 20 or more. The atopic dermatitis is classified into an intrinsic type or an extrinsic type according to a clinical phenotype, and depending on a reporter, the prevalence of the intrinsic dermatitis varies in the range of 10 to 30.4%, and clinical characteristics of the intrinsic dermatitis determined by a skin prick test are normal in total IgE level in serum, negative in allergy-inducing food, and negative in allergen-specific serum IgE with respect to general aeroallergens and food allergens. The extrinsic atopic dermatitis has the highest frequency at the age of 18 or more, averagely 31.6, and the intrinsic atopic dermatitis has the highest frequency at the average age of 27.1. The average age of total patients with intrinsic dermatitis is 30.4, and it is reported that the frequency is considerably reduced according to time, and the intrinsic dermatitis barely occurs over 57 or more years old. In addition, it was reported that 57.8% of patients with atopic dermatitis was accompanied with allergic conjunctivitis or asthma, 61.7% of the patients were increased in total IgE, 26.5% of the patients had a total IgE of 300 IU/ml or more, and 36.7% of the patients had 1st-degree relatives.
In addition, allergic rhinitis is a symptomatic disorder of the nose inducing an IgE-mediated inflammation after allergen exposure, and causing symptoms in a nose, eyes, ears, and fauces. Previously, it was classified into seasonal or perennial allergic rhinitis, but presently is divided into intermittent allergic rhinitis or persistent allergic rhinitis, and subdivided into mild, moderate, or severe allergic rhinitis based on duration of symptoms by “the Allergic Rhinitis and Its Impact on Asthma Working Group.” The prevalence is 10 to 30% in adults, and approximately 40% in children, which are a bit different according to a reporter in each country. Allergic rhinitis risk factors are indoor and outdoor allergens and when serum IgE is 100 IU/ml or more before the age of 6. Allergic rhinitis develops complications such as sinusitis, otitis media, conjunctivitis, and sleep disturbance, an attention problem, and maladjustment of a social life due to exacerbation of asthma and sinusitis when not treated and thus becoming worse.
In addition, urticaria is a disease temporarily expressing well-circumscribed wheals in red or white on a superficial portion of dermis and mucosa. When the symptoms do not persist 6 weeks, it is defined as acute urticaria, and when persisting over 6 weeks, it is defined as chronic urticaria. The urticaria is caused by internal and external factors, and mostly foods, drugs, food additives, and infectious and physical stimuli (cold, heat, exercise, solar rays, and mechanical irritation) are estimated as main causes. Inhalants such as pollen, animal dander or fur, spores of fungi, house dust mites, air sprays, etc. are inhaled through respiration to cause urticaria, and foods are generally causes of acute urticaria, but barely induce chronic urticaria. As foods that frequently cause urticaria, chocolates, clams (particularly, Meretrix lusoria), peanuts, peas, chestnuts, tomatoes, kiwis, egg whites, cheeses, garlic, onions, and food additives [yeast, salicylic acid, citric acid, azo dyes, or benzoic acid derivatives] are used, and as drugs, various drugs such as aspirin, sulfone amide, narcotic, NSAID, vitamin, estrogen, insulin, quinine, salicylate, etc. are used. The urticaria is easily diagnosed only by clinical symptoms, and if it is difficult to find a cause, various examinations may be helpful to find the cause. For treatment, avoidance after finding a cause is ideal, but since it is difficult to find a cause, various public remedies are performed.
To treat such an allergic disease, various therapies are being studied, and anti-allergic agents, histamine receptor antagonists (antihistamines), steroids, etc. are used. However, any one of an antihistamine inhibiting signal transduction from peripheral nerves by being linked with a histamine receptor antagonistically to histamine, an anti-allergic agent reducing an activity of chemical mediator-producing cells to attempt alleviation of symptoms, and a steroid reducing immune responses to alleviate inflammation has side effects, but there is no dramatic effect.
Meanwhile, lactobacilli is a product first found by Metchnikoff and obtained from attempts to obtain a therapeutic effect by acidifying intestinal contents to prevent growth of putrefactive organisms, and 165 species of Lactobacillus genera considered as representative lactobacilli are found. Particularly, as a probiotic lactobacillus which has been used in treatment of an allergic disease, it has been reported that Lactobacillus acidophilus L-92 has effects on some of allergic rhinitis symptoms triggered by Himalayan cedar pollens in Japan, and use of Lactobacillus rhamnosus GG, Lactobacillus acidophilus species, Lactobacillus reuteri species, Lactobacillus fermentum species, Bifidobacterium breve species, or Bifidobacterium lactis species has been attempted to treat atopic dermatitis.
As Lactobacillus acidophilus species strains separated from a human intestine among the strains of the Lactobacillus genera, strains clinically used for treatment such as Lactobacillus acidophilus LB strain, Lactobacillus acidophilus 145 strain, Lactobacillus acidophilus DDS-I strain, Lactobacillus acidophilus L-92 strain, Lactobacillus acidophilus NCFM strain, Lactobacillus acidophilus LA O2 strain, Lactobacillus acidophilus L-55 strain, Lactobacillus acidophilus NCK56 strain, Lactobacillus acidophilus CH5 strain, Lactobacillus acidophilus LAFTIL-10 strain, Lactobacillus acidophilus OLL2769 strain, and Lactobacillus acidophilus 27L strain were used. Among these, only two kinds of the strains such as Lactobacillus acidophilus DDS-1 strain and Lactobacillus acidophilus NCFM strain were used in treatment of an allergic disease, but an effect on treating or improving an allergic disease was not proved.
Meanwhile, Lacteol is a product name of a freeze-dried product of a culture solution containing tyndallized dead cells of Lactobacillus acidophilus LB strain found by the French doctor, Pierre BOUCARD, in 1907, and a dead cell drug conserving a metabolite produced by Lactobacillus acidophilus LB strain, which is known as a safe drug having no fatal side effects since it was produced in 1979 and no fatal reports with long-term use, is known to be effective in acute diarrhea and diarrhea caused by colitis and functional colonic diseases, but it was never used in treatment of an allergic disease.
The inventor found that Lacteol containing dead cells of Lactobacillus acidophilus LB strain had excellent therapeutic effects and improvements in symptom, compared to the primary therapeutic agents of atopic dermatitis, calcineurin inhibitors, a therapeutic agent to allergic rhinitis, antihistamines, and intranasal inhalants, and therefore the present invention was completed.